3-phenyl-2, 6-dioxopiperidin-3-yl propionamide derivatives and method for preparing same

ABSTRACT

This invention relates to 3-(3-phenyl-2,6-dioxopiperidin-3-yl)propionamide derivatives, and to processes for preparing the same.

The subject of the present invention is3-(3-phenyl-2,6-dioxopiperidin-3-yl)propionamide derivatives, theirmethod of preparation and their use.

3-(3,4-dichlorophenyl)-2,6-dioxopiperidine-3-propionic acid is describedin patent application WO 97/32852.

There has now been found a novel compound of formula:

in which:

X represents a halogen, preferably a chlorine atom or fluorine atom;

R₁ and R₂ each independently represent hydrogen, a C₁-C₆ alkyl which isunsubstituted or substituted with a hydroxyl, a benzyl which isunsubstituted or substituted with a C₁-C₆alkyl, a hydroxyl or R₁ and R₂together constitute with the nitrogen atom to which they are attached aheterocyclic radical chosen from azetidin-1-yl, pyrrolidin-1-yl,piperidin-1-yl and morpholin-4-yl,

it being possible for said heterocyclic radicals to be mono- ordisubstituted.

As substituents of said heterocyclic radicals, there may be mentionedgroups, which are similar or different, chosen from a C₁-C₄ alkyl, aphenyl, a benzyl, an amino, a (C₁-C₄)alkylamino and adi(C₁-C₄)alkylamino.

Compound (I) exists in racemic form or in 2 enantiomerically pure forms.There is preferred the compound having the configuration described bythe formula:

There are preferred the compounds of formula (I) or of formula (II) inwhich NR₁R₂ represents a dialkylamino group such as dimethylamino,butylamino, ethanolamino, (N-methyl)ethanolamino, benzylamino,morpholino or piperidino. There are also preferred the compounds offormula (I) or of formula (II) in which NR₁R₂ represents a4-methylamino-4-phenylpiperdin-1-yl group.

The compounds of formula (I) or of formula (II) are intermediates whichare useful for the preparation of the compounds of formula:

in which X is as defined above for (I).

It appears in patent application WO 97/03852 that the compounds offormula (III) or (IV) are useful for the preparation of neurokininantagonist compounds such as that described in the the publication by X.Emonds-Alt et al., Life Sci., 1995, 56 (1), 27-32, namely(S)-N-[1-[3-{1-benzoyl-3-(3,4-dichlorophenyl)piperidin-3-yl}propyl]-4-phenylpiperidin-4-yl]-N-methylacetamideor SR 142801 whose international nonproprietary name is osanetant. Thiscompound is an NK₃ antagonist.

In particular, the subject of the present invention is a compound offormula:

in which X is as defined above for (I).

The subject of the present invention is also a method of preparing acompound of formula (I). Said method is characterized in that a compoundof formula:

in which X is as defined above for (I), is cyclized by elimination ofwater.

The compound of formula (VI) may be obtained by the action of an amineof formula HNR₁R₂ in which R₁ and R₂ are as defined above for (I) on acompound of formula:

The preparation of the compound of formula (VI) is carried out in water,in an alcoholic solvent, in an ethereal solvent, in a chlorinatedsolvent or in an aromatic solvent, at a temperature between roomtemperature and the reflux temperature of the solvent. Preferably, wateror methanol is used.

The cyclization of the compound of formula (VI) by elimination of amolecule of water is carried out after activation of the carboxyl groupof the compound of formula (VI) by formation of a mixed anhydride. Forthat, an anhydride is used in excess, for example acetic anhydride ormethanesulfonic anhydride, at a temperature between room temperature and100° C.

The compounds of formula (VI) are novel and form part of the presentinvention.

The compounds of formula (III) are described in patent application WO97/32852.

According to the present invention, it has been observed that startingwith a compound of formula (III) in racemic form, a racemic compound offormula (VI) is obtained in which the 2 enantiomers are in the sameproportion as for the starting compound. A racemic compound of formula(I) is then obtained by cyclization in which the 2 enantiomers are inthe same proportion as for the starting compound.

According to the present invention, it has been found, using as startingmaterial a pure enantiomer of the compound of formula (III), that theformation of the hexanoic acid derivative of formula (VI) occurs withretention of configuration, and that the cyclization then occurs withinversion of configuration.

The method according to the invention thus applies to the preparation ofcompounds in optically pure form. Thus, advantageously, the presentinvention relates to a method for the preparation of a compound offormula (II) characterized in that a compound of formula:

in which X is as defined above for (I), is cyclized by elimination ofwater, to give a compound of formula:

The compound of formula (VII) may be obtained by the action of an amineof formula HNR₁R₂ in which R₁ and R₂ are as defined above for (I) on acompound of formula:

According to the present invention, the compound of formula (I) may beprepared using another method characterized in that an amine of formulaHNR₁R₂ in which R₁ and R₂ are as defined above for (I) is reacted with acompound of formula:

in which X is as defined above for (I).

The compounds of formula (VIII) may be obtained from an acid of formula:

The compounds of formula (VIII) are novel and constitute a subsequentaspect of the present invention.

The action of an amine on an acid chloride of formula (VIII) ispreferred for the preparation of a compound of formula (V) and mostparticularly for the preparation of an enantiomer of the compound offormula (V) of formula:

This method is characterized in that 4-methylamino-4-phenylpiperidine isreacted with a compound of formula:

The compound of formula (X) may be prepared from the acid of formula:

The acid chloride is prepared in a known manner, for example by theaction of thionyl chloride in the absence of solvent or in an anhydroussolvent such as toluene, dimethylformamide or dichloromethane oralternatively in a mixture of these solvents.

The action of 4-methylamino-4-phenylpiperidine is carried out in ananhydrous solvent, in a basic medium, for example in the presence oftriethylamine.

The 4-methylamino-4-phenylpiperidine is prepared according to Biorg.Med. Chem. Letters, 1996, 4 (19), 2307-2310.

According to the present invention, the compound of formula (I) makes itpossible to obtain, by acidolysis, the acid of formula (III). Likewise,according to the present invention, the compound of formula (II) makesit possible to obtain, by acidolysis, the acid of formula:

The acidolysis is carried out in a manner known to persons skilled inthe art, for example with a C₁-C₄ carboxylic acid.

Thus, the present invention relates to a method of preparing a compoundof formula (III) by hydrolysis of a compound of formula (I). It alsorelates to a method of preparing a compound of formula (IV) byhydrolysis of a compound of formula (II).

According to a subsequent aspect of the present invention, the compoundof formula (I) makes it possible to obtain, by reduction, a compound offormula:

in which X, R₁ and R₂ are as defined for (I).

The reduction is carried out by means known to persons skilled in theart. The reducing agents used are borane complexes such as for exampleborane-tetrahydrofuran or borane-dimethyl sulfide or alternatively amixed alkali metal hydride such as lithium aluminum hydride or sodiumbis(2-methoxyethoxy)aluminum hydride in solution in toluene (Red-Al®,the borane-tetrahydrofuran complex being preferred.

The reduction with borane is carried out in a solvent, preferably anaprotic solvent such as tetrahydrofuran at the reflux temperature of thesolvent. In general, after 1 to 6 hours of heating, the reduction iscomplete and the 3,3-disubstituted piperidine is isolated, according toconventional methods, by first destroying the excess borane withmethanol. The free base may be isolated by evaporation of the solvent,and then the residue is taken up in water, the medium is acidified withhydrochloric acid, treated with a base, preferably sodium hydroxide, andextracted with a solvent.

Most particularly, by reducing a compound of formula (IX) in which X=C1,there is prepared a compound of formula:

Thus, the present invention relates to a method of preparing a compoundof formula (XI) by reducing a compound of formula (I).

Likewise, the present invention relates to a method of preparing acompound of formula (XII) by reducing a compound of formula (IX).

In the examples and in the description, the following abbreviations areused.

RT: room temperature

Me: methyl

THF: tetrahydrofuran

DMF: dimethylformamide

L-PheOMe: methyl ester of L-phenylalanine

BOP (Castro's reagent):benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate

MIBK: methyl isobutyl ketone.

The NMR (nuclear magentic resonance) spectra are recorded at 250 or 300MHz.

To analyze the products, high-performance liquid chromatography on C18(HPLC-C18) is used under the following conditions:

10 to 15 μmol of product dissolved in 50 μl of methanol are diluted with150 μl of eluent, and 20 μl are injected onto an Alltima® C18 5μ column(length=250 mm, inside diameter=4.6 mm) eluting with an isocraticmixture A/B: 32/68, the flow rate 1 ml/min; A: aqueous buffer 2.6; B:methanol; the compounds are detected at 280 mm.

Chiral HPLC-C18 is also used under the following analytical conditions:

2 to 3 μmol of product are dissolved in a mixture of DMF (100 μl),triethylamine (15 μl), with either (S)-methylbenzylamine (15 μl), orL-PheOMe (15 mg). 10 mg of BOP (Castro's reagent) are added and themedium is left for 30 minutes at 50° C. The reaction mixture issubjected to an acid extraction with ethyl acetate/HCl 1N:1 ml/l ml. 100μl of organic phase are then evaporated off, then the medium is eithertaken up in 250 μl of eluent or taken up in 50 μl of methanol and thendiluted with 150 μl of eluent. 20 μl of this solution are injected. Theprocedure is carried out on columns 250 mm long, having an insidediameter of 4.6 mm, eluting with a hexane/isopropanol:70/30 mixture,flow rate 1 ml/min. The compounds are detected at 280 nm.

The other analytical conditions vary according to the compoundsanalyzed.

Preparation 1 4,6-Dicarbamoyl-4-(3,4-dichlorophenyl)hexanoic acid

(VI): X=Cl, NR₁R₂=NH₂

3.30 g of racemic 3-(3,4-dichlorophenyl)-2,6-dioxopiperidine-3-propionicacid are placed in 20 ml of an aqueous solution of aqueous ammonia at30% and stirred at room temperature. After 2 hours, the solution isdegassed under vacuum to remove the excess aqueous ammonia and thendiluted to 50 ml with water. The medium is slowly acidified to pH 2-3with 1 N HCl. The precipitate formed is filtered, drained and then driedover KOH to give 3.13 g of the expected compound.

¹H NMR (DMSO): 1.79 to 2.12 ppm (4 CH₂, m); 7.43 ppm (1 aromatic H, s);7.60 and 7.24 ppm (2 aromatic H, d); 6.7 and 7.22 ppm (NH₂ groups).

The starting compound and the compound obtained are subjected toanalysis by HPLC-C18; the retention times are Tr=6.2 minutes and Tr=3.7minutes respectively.

Furthermore, the product obtained is subjected to chiral analysis byHPLC-C18 after coupling of its free carboxyl with L-PheOMe. 2 peaks areobserved (Tr=9.8 minutes and Tr=10.7 minutes) showing that the productobtained is in racemic form.

Preparation 2 4,6-Dicarbamoyl-4-(3,4-dichlorophenyl)hexanoic acid, of Sconfiguration

(VIII): X=Cl, NR₁R₂=NH₂

The procedure is carried out as described in preparation 1, startingwith 3.30 g of3-[3-(3,4-dichlorophenyl)-2,6-dioxopiperidin-3-yl]propionic acid, of (S)configuration. 3.13 g of the expected compound are obtained whoseanalysis is carried out by HPLC-C18. A peak is observed at Tr=3.74minutes. Chiral analysis after coupling with L-PheOMe gives a principalpeak at 10.7 minutes and a secondary peak at Tr=9.8 minutes. It isobserved that the optical purity is the same as that for the startingcompound.

Preparation 2a 4,6-Dicarbamoyl-4-(3,4-dichlorophenyl)hexanoic acid, of Rconfiguration

[lacuna]: X=Cl, NR₁R₂=NH₂.

The procedure is carried out as in preparation 2 using as startingmaterial 3-[3-(3,4-dichlorophenyl)-2,6-dioxopiperidin-3-yl]propionicacid, R isomer.

Chiral analysis after coupling with L-PheOMe gives a principal peak atTr=9.8 minutes and a secondary peak at Tr=10.7 minutes.

Preparation 34-Carbamoyl-4-(3,4-dichlorophenyl)-6-(piperidin-1-yl)carbonylhexanoicacid

0.3 g of racemic3-[3-(3,4-dichlorophenyl)-2,6-dioxopiperidin-3-yl]propionic acid, 1 mlof methanol and 0.5 ml of piperidine are placed at 60° C. for 15 hoursin a round-bottomed flask. The reaction medium is diluted with 10 ml ofwater and acidified with 1 N HCl to pH 2-3. The white crystals formedare filtered, drained and then dried to give 0.3 g of the expectedcompound.

¹H NMR (DMSO): 1.36 to 1.56 ppm (3 CH₂, m); 2.04 to 2.50 ppm (4 CH₂, m);3.3 ppm (2 CH₂, m); 7.25 and 7.6 ppm (2 aromatic H, d); 7.45 ppm (1aromatic H, d); 10.98 ppm (COOH, s).

HPLC-C18 analysis shows a peak at Tr=8.2 minutes. The HPLC-C18 chiralanalysis, after coupling with L-PheOMe, shows the formation of 2 peaksof identical surface area: Tr=7.9 minutes and Tr=8.8 minutes.

The compound obtained is therefore in racemic form.

Preparation 44-Carbamoyl-4-(3,4-dichlorophenyl)-6-(piperidin-1-yl)carbonylhexanoicacid, of S configuration

0.3 g of 3-[3-(3,4-dichlorophenyl)-2,6-dioxopiperidin-3-yl]propionicacid of S configuration is treated with piperidine as described inPreparation 3 to give 0.3 g of the expected compound.

HPLC-C18 analysis shows a peak at Tr=8.2 minutes. HPLC-C18 chiralanalysis after coupling with L-PheOMe shows a peak at Tr=8.8 minutes. Itis observed that the optical purity is identical to that of the startingmaterial.

−6.4° (c=1; CH₃OH/NaOH

α_(D) ²⁰=1 N:9.7/0.3)

Preparation 4a4-Carbamoyl-4-(3,4-dichlorophenyl)-6-(piperidin-1-yl)carbonylhexanoicacid, of R configuration

The procedure is carried out as in preparation 4 using as startingmaterial 3-[3-(3,4-dichlorophenyl)-2,6-dioxopiperidin-3-yl]propionicacid of R configuration.

Chiral analysis after coupling with L-PheOMe shows a peak at Tr=7.9minutes.

By carrying out the procedure as in Preparations 1 and 3 describedabove, starting with racemic3-[3-(3,4-dichlorophenyl)-2,6-dioxopiperidin-3-yl]propionic acid andvarious amines, the compounds described in Table 1 below were prepared.

These compounds are characterized in HPLC by their capacity factor.

By way of comparison, the k′ values are indicated for the compounds ofPreparations 1 and 3.

TABLE 1 (VI)

Preparations —NR₁R₂ k′ 1 —NH₂ 0.86 3

2.73 5 —NHCH₂CH₂OH 0.72 6 —N(CH₃)—CH₂CH₂OH 0.86 7

1.17 8 —HN(CH₂)₃CH₃ 3.0  9 —NH—CH₂—C₆H₅ 3.25

EXAMPLE 13-(3,4-Dichlorophenyl)-3-[(piperidin-1-yl)-3-oxopropyl]piperidine-2,6-dione

0.3 g of the compound obtained in Preparation 3 is placed in a closedcontainer with 1.5 ml of acetic anhydride and heated at 95-100° C. for30 minutes. After cooling to RT, ethyl ether is added and the medium isallowed to stand in a cold room at 4° C. The crystals formed arefiltered and drained to give 270 mg of the expected compound.

HPLC-C18 analysis shows a single peak at Tr=14 minutes. This productwhich is obtained is identical to that which is obtained by coupling3-[3-(3,4-dichlorophenyl)-2,6-dioxopiperidin-3-yl]propionic acid withpiperidine.

EXAMPLE 23-(3,4-Dichlorophenyl)-3-[(piperidin-1-yl)-3-oxopropyl]piperidine-2,6-dione,of R configuration

0.2 g of the compound obtained in Preparation 4 and 0.8 ml of aceticanhydride are placed in a closed tube at 95-100° C. for 30 minutes.After cooling to RT, 10 ml of distilled water are added and the mediumis left stirring for 30 to 40 minutes. The medium is extracted with 10ml of ethyl acetate and then the ethyl acetate phase is dried and thenevaporated under reduced pressure. 0.18 g of the expected compound isobtained. HPLC-C18 analysis shows a single peak at Tr=14 minutes.

EXAMPLE 2a3-(3,4-Dichlorophenyl)-3-[(piperidin-1-yl)-3-oxopropyl]piperidine-2,6-dione,of R configuration

The procedure is carried out as in Example 2, starting with the compoundobtained in preparation 4a.

HPLC-C18 analysis of the compound obtained shows a single peak at Tr=14minutes.

EXAMPLE 3 3-[3-(3,4-Dichlorophenyl)-2,6-dioxopiperidin-3-yl]propionicacid, of S configuration

(III): X=Cl.

The compound obtained in EXAMPLE 2 is taken up in 0.5 ml of propionicacid and placed in a tube sealed under vacuum. After 18 hours at 145°C., the reaction mixture and diluted with 10 ml of 1 N HCl. After oneday, the product which crystallizes is filtered, drained and dried. 100mg of the expected compound are obtained.

HPLC-C18 analysis shows a peak at Tr=6.2 minutes.

Chiral analysis after coupling with (S)-methylbenzylamine shows a peakat 7.13 minutes.

EXAMPLE 3a 3-[3-(3,4-Dichlorophenyl)-2,6-dioxopiperidin-3-yl]propionicacid, of S configuration

The procedure is carried out as in Example 3 starting with the compoundobtained in Example 2a.

HPLC-C18 analysis of the compound obtained shows a peak at Tr=6.2minutes.

Chiral analysis after coupling with (S)-methylbenzylamine shows a peakat 9.13 minutes.

EXAMPLE 43-(3,4-Dichlorophenyl)-3-[3-(4-methylamino-4-phenylpiperidin-1-yl)-3-oxopropyl]piperidine-2,6-dione,of S configuration

(IX): X=Cl

3-[3-(3,4-Dichlorophenyl)-2,6-dioxopiperidin-3-yl]propionic acidchloride, of S configuration

Under a nitrogen atmosphere, 20 g of3-[3-(3,4-dichlorophenyl)-2,6-dioxopiperidin-3-yl]propionic acid, 200 mlof toluere and 0.5 ml of DMF are mixed. The medium is heated to 60° Cand 14.9 g of thionyl chloride and 40 ml of toluene are introduceddropwise. The stirring is maintained for 5 hours at 60° C. The tolueneand the excess thionyl chloride are evaporated off and then the reactionmedium is dried in an oven (40° C.) overnight.

The product obtained is used as it is in the next stage.

B)3-(3,4-Dichlorophenyl)-3-[3-(4-methylamino-4-phenylpiperidin-1-yl)-3-oxopropyl]piperidine-2,6-dione,of S configuration.

Under a nitrogen atmosphere, 11.5 g of 4-methylamino-4-phenylpiperidinein solution in 100 ml of THF and 8.52 ml of triethylamine are introducedand then the reaction medium is cooled to 0° C.±5° C. with an ice bath.The acid chloride prepared in the preceding stage in 150 ml of THF isadded dropwise and the medium is left stirring for one hour. Afterevaporation of the THF, the medium is washed with 100 ml of water and100 ml of dichloromethane. The organic phase is separated after settlingout and then washed 3 times with 100 ml of water; the dichloromethane isevaporated off and then the medium is dried in an oven at 40° C. and32.1 g of the expected compound are obtained. 29.1 g of this compoundare recrystallized in the hot state from MIBK to give 17 g of the purecompound. Moreover, the recrystallization mother liquors are filtered onsilica to give an additional 5.2 g of pure compound.

¹H NMR (CDCl₃): 1.65 to 2.69 ppm (16 H, m); 3.25 to 3.98 ppm (4 H, m);7.06 to 7.46 ppm (8 aromatic H and CO—NH—CO).

α_(D) ²⁵=+77.8° (c=1, methanol).

What is claimed is:
 1. A compound of formula:

in which: X represents a halogen; R₁ and R₂ each independently representhydrogen, a C₁-C₆ alkyl which is unsubstituted or substituted with ahydroxyl, a benzyl which is unsubstituted or substituted with a C₁C₄alkyl, a hydroxyl or R₁ and R₂ together constitute with the nitrogenatom to which they are attached a heterocyclic radical chosen fromazetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl and morpholin-4-yl, itbeing possible for said heterocyclic radicals to be mono- ordisubstituted.
 2. A compound according to claim 1 of the formula:


3. A compound according to claim 2 wherein the substituents R₁ and R₂together constitute a heterocyclic radical which is mono- ordisubstituted with one or more groups, which are similar or different,chosen from a C₁-C₄ alkyl, a phenyl, a benzyl, an amino, a(C₁-C₄)alkylamino and a di(C₁-C₄)alkylamino.
 4. A compound according toclaim 3 of formula:


5. A compound according to claim 4 of formula:


6. A compound according to claim 4 wherein X represents a chlorine atomor a fluorine atom.
 7. A method of preparing a compound of formula (I)according to claim 1 wherein a compound of formula:

in which X is as defined for (I) in claim 1, is cyclized by eliminationof water.
 8. A method according to claim 7 wherein the compound offormula (VI) is obtained by the action of an amine of formula HNR₁R₂ inwhich R₁ and R₂ are as defined above for (I) on a compound of formula:


9. A method according to claim 7 wherein a compound of formula:

in which X is as defined for (I) in claim 1, is cyclized by eliminationof water, to give a compound of formula:


10. A method according to claim 9 wherein the compound of formula (VII)is obtained by the action of an amine of formula HNR₁R₂ in which R₁ andR₂ are as defined for (I) in claim 1 on a compound of formula:


11. A method of preparing a compound of formula (I) according to claim1, wherein an amine of formula HNR₁R₂ in which R₁ and R₂ are as definedfor (I) in claim 1 is reacted with a compound of formula:

in which X is as defined for (I) in claim
 1. 12. A method according toclaim 11 wherein the compound of formula (VII) is prepared from an acidof formula:


13. A method according to claim 11 wherein4-methylamino-4-phenylpiperidine is reacted with a compound of formula:

to give a compound of formula:


14. A method according to claim 13 wherein the compound of formula (X)is prepared from an acid of formula:


15. A compound according to claim 5 wherein X represents a chlorine atomor a fluorine atom.